Abstract Prescription opioid abuse and addiction are major burdens to patients and society, resulting in significant costs, illnesses, and deaths. The intertwined issues of i) the widespread and increasing abuse of prescription opioids, and ii) reluctance of prescribers to write prescriptions for opioid analgesics, have resulted in the under-treatment of patients with moderate-to- severe pain. Several abuse-deterrent opioid products (primarily formulations) are currently marketed or in clinical development, but they fall short of being resistant to abuse. In contrast to these formulation-based strategies, Ensysce Biosciences has created two complementary, novel technologies that control the release of known opioids. The abuse resistant features of Ensysce Biosciences' BIO-MD? with MPAR? prodrugs are imparted at the molecular level. Our Bio-MD? [Bio-Activated Molecular Delivery] systems are ?bio-activated? to release clinically effective opioid drugs only when exposed to the correct physiologic conditions (i.e., ingested and exposed to trypsin in the small bowel). Our prodrugs provide a number of important features to deter abuse. These include: i) low activity at the -opioid receptor, ii) minimal systemic conversion to opioid following IV administration, iii) resistant to common household tampering/extraction methods, and iv) the PK profile of opioid release is inherent to the prodrug, not based on a formulation. The potential benefits to society of an opioid that resists both oral and parenteral abuse are considerable. We have evaluated Bio-MD? opioid products in human clinical trials and demonstrated successfully the oral delivery of active opioids with extended release profiles. MPAR? (multi-pill abuse resistance) involves in situ bio-regulation of opioid delivery from our Bio-MD? systems, enabling control over oral multi-dose pharmacokinetic (PK) profiles. MPAR? oral overdose protection is conferred by the action of a trypsin inhibitor that is co-formulated with the Bio-MD? system. As multiple doses are co-ingested, the trypsin ?bio-activation? is progressively inhibited, resulting in a therapeutically effective dose of opioid without the risk of oral overdose. MPARTM protection of our oxycodone prodrug PF614 has been successfully demonstrated in both rat and dog species. The objective of this proposal is to advance the MPARTM technology and ultimately to translate our rat/dog MPARTM results into humans, and to eliminate the oral overdose potential of opioid BIO-MDTM products.